This Report involves work collected under protocols 04-M-0222 (NCT00088699) and 17-M-0060 (NCT03065335). Our research suggests that the glutamatergic system is involved in the mechanism of action of rapid antidepressant response. In addition, this system may be a feasible target for developing treatments that have rapid and robust efficacy in individuals who have treatment-resistant depression and suicidal thoughts. We found that the glutamatergic modulator ketamine resulted in rapid, robust and relatively sustained antidepressant, antisuicidal, and anti-anhedonic effects. Response with ketamine occurred within 2 hours and lasted approximately 1 week. Comparable response rates with standard of care treatments occur at 6-8 weeks instead of hours. Study: (Biomarkers of rapid response in major depressive disorder): protocols 04-M-0222 (NCT00088699) and 17-M-0060 (NCT03065335). OBJECTIVE: To determine the neural correlates of rapid antidepressant response to the NMDA antagonist ketamine in subjects with major depressive disorder. We found robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist (ketamine); onset occurred within 2 hours post-infusion and continued to remain significant for 1 week. Aims are 1) to examine the antisuicidal effects of ketamine, and 2) to examine correlates of antidepressant response to ketamine in both major depressive disorder and bipolar disorder and include these data/outcome measures: clinical (e.g., family history), imaging (magnetic resonance imaging/spectroscopy), electrophysiological (magnetoencephalography MEG, electroencephalography EEG), neuropsychological, and biochemical (e.g., genetics, microRNA, BDNF, metabolomics), 3) To demonstrate more robust neuropharmacodynamic effects measured by neuropharmacodynamic imaging (fMRI+EEG and MEG) of ketamine 0.5 mg/kg as compared to placebo administered over 40 minutes. Secondary Outcome Measures: To determine if increases in synaptic plasticity, using electrophysiological measures in response to TMS and in association with sleep (i.e. slow wave sleep EEG activity) are associated with better antidepressant response to 0.5 mg/kg Time Frame: baseline and post-drug To demonstrate enhanced efficacy, as measured by the MADRS, of IV ketamine 0.5 mg/kg in participants with MDD using a psychophysiological technique (i.e. NPU-threat test). Time Frame: baseline and post-drug To identify baseline peripheral measures associated with response to the administration of ketamine 0.5 mg/kg, as potential biomarkers of acute (24 hour) treatment response. Time Frame: baseline and post-drug Results in the past year: 1. Ketamine, a rapid acting antidepressant, has distinct electrophysiological and behavioral effects in depressed and healthy subjects. Ketamines mechanism of action was assessed using gamma power from magnetoencephalography as a proxy measure for homeostatic balance in unmedicated subjects with major depressive disorder (MDD) and healthy controls. MDD subjects showed significant improvements in depressive symptoms, and healthy subjects exhibited modest but significant increases in depressive symptoms for up to one day after ketamine administration. Both groups showed increased resting gamma power following ketamine. In controls, increased gamma power was associated with increased depressive symptoms. In MDD subjects, baseline gamma power moderated the relationship between post-ketamine gamma power and antidepressant response. This finding suggests biological subtypes based on the direction of homeostatic dysregulation and has important implications for inferring ketamines mechanism of action from studies of healthy controls alone. 2. Motor-Activity Markers of Circadian Timekeeping Are Related to Ketamine's Rapid Antidepressant Properties. The rapid clinical antidepressant effects of the glutamatergic modulator ketamine may be due to its ability to restore synaptic plasticity and related effects on sleep-wake and circadian systems. Preclinical studies indicate that ketamine alters expression of circadian clock-associated molecules, and clinical studies of ketamine on plasticity-related biomarkers further suggest an association with sleep slow waves and sleep homeostasis. Wrist-activity monitors were used to examine the pharmacologic and rapid antidepressant effects of ketamine on markers of circadian timekeeping (amplitude and timing) in mood disorders. The findings are the first to demonstrate an association between ketamine's clinical antidepressant effects and circadian timekeeping. The results suggest that trait like circadian activity patterns indicate rapid mood response to ketamine, and that mediators of continuing ketamine-induced mood changes include altered timing and amplitude of the circadian system. 3. A Double-Blind, Placebo-Controlled, Pilot Study of Riluzole Monotherapy for Acute Bipolar Depression. Glutamatergic system abnormalities are implicated in the pathophysiology and treatment of both major depressive disorder and bipolar depression (BDep). Subsequent to studies demonstrating the rapid and robust antidepressant effects of ketamine, an N-methyl-D-aspartate receptor antagonist, other glutamatergic modulators are now being studied in clinical trials of mood disorders. We conducted a randomized, double-blind, placebo-controlled trial of riluzole monotherapy for the treatment of BDep. Subjects aged 18 to 70 years with bipolar disorder currently experiencing a depressive episode were tapered off of excluded medications and randomized to receive riluzole (50-200 mg/d) or placebo for 8 weeks. No significant differences in depressive symptoms were observed between subjects treated with riluzole and those receiving placebo (P = 0.12). 4. Preliminary differences in resting state MEG functional connectivity pre- and post-ketamine in major depressive disorder. Functional neuroimaging techniques including magnetoencephalography (MEG) have demonstrated that the brain is organized into networks displaying correlated activity. Group connectivity differences between healthy controls and participants with major depressive disorder (MDD) can be detected using temporal independent components analysis (ICA) on beta-bandpass filtered Hilbert envelope MEG data. We obtained MEG recordings before and after open-label infusion of 0.5mg/kg ketamine in MDD subjects and examined networks previously shown to differ between healthy individuals and those with MDD. Connectivity between the amygdala and an insulo-temporal component decreased post-ketamine in MDD subjects towards that observed in control subjects at baseline. Ketamine appeared to reduce connectivity, regardless of whether connectivity was abnormally high or low compared to controls at baseline.